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MBC in Press, published online ahead of print November 28, 2007
Mol. Biol. Cell 10.1091/mbc.E07-09-0890

A more recent version of this article appeared on February 1, 2008
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Submitted on September 12, 2007
Revised on November 6, 2007
Accepted on November 16, 2007

Myosin Transducer Mutations Differentially Affect Motor Function, Myofibril Structure, and the Performance of Skeletal and Cardiac Muscles

Anthony Cammarato,*{dagger} Corey M. Dambacher,*{ddagger} Aileen F. Knowles,{sect} William A. Kronert,* Rolf Bodmer,{dagger} Karen Ocorr,{dagger} and Sanford I. Bernstein*

*Biology Department and Heart Institute, San Diego State University, San Diego, CA 92182-4614; {dagger}Development and Aging Program, Burnham Institute for Medical Research, La Jolla, CA 92037; {sect}Chemistry and Biochemistry Department, San Diego State University, San Diego, CA 92182-1030

Monitoring Editor: Thomas Pollard

Striated muscle myosin is a multi-domain ATP-dependent molecular motor. Alterations to various domains affect the motor’s chemomechanical properties and are associated with skeletal and cardiac myopathies. The myosin transducer domain is located near the nucleotide-binding site. Here we helped define the transducer’s role by using an integrative approach to study how Drosophila melanogaster transducer mutations D45 and Mhc5 affect myosin function as well as skeletal and cardiac muscle structure and performance. We found D45 (A261T) myosin has depressed ATPase activity and in vitro actin motility while Mhc5 (G200D) myosin has these properties enhanced. Depressed D45 myosin activity protects against age-associated dysfunction in metabolically demanding skeletal muscles. In contrast, enhanced Mhc5 myosin function allows normal skeletal myofibril assembly, but induces degradation of the myofibrillar apparatus, likely 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 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 Mhc5 mutations illustrate the transducer’s role in influencing myosin’s chemomechanical properties 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.

{ddagger}Present address: The Scripps Research Institute, Kellogg School of Science and Technology, 10550 N. Torrey Pines Road, TPC-19, La Jolla, CA 92037.

Address correspondence to: Karen Ocorr (kocorr{at}burnham.org) or Sanford I. Bernstein (sbernst{at}sciences.sdsu.edu)






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