Microtubule acetylation is a novel target in Duchenne muscular dystrophy

总结

Summary Duchenne muscular dystrophy (DMD) pathology is associated with cytoskeletal and biochemical accelerate the relentless degeneration of skeletal muscle and the development of cardiomyopathy. Microtubule proliferation increases cytoskeletal stiffness which drives the excess mechanotransduction elicited reactive oxygen species (ROS) and calcium (Ca2+) signaling linked to DMD pathology. Evidence that the targeted reduction of MT proliferation reduced workload injury in DMD heart and skeletal muscle has generated great interest in the mechanisms of MT mechanotransduction, its alteration in DMD, and its targeting as a novel therapeutic opportunity to slow DMD progression. The focus of this proposal is acetylation of -tubulin, a tubulin post- translational modification regulates MT structure and function. Acetylation of -tubulin occurs in response to cell stress and modulates the MT mechanical proprieties and cell mechano-sensitivity. The PI’s new preliminary data shows that MT acetylation regulates cytoskeletal stiffness and mechano-activated ROS production in striated muscle and identifies this PTM elevated in DMD muscle. Taken together these findings inform the overarching hypothesis that MT acetylation impacts cytoskeletal stiffness to regulate mechanotransduction through Nox2- ROS and Ca2+ in healthy cardiac and skeletal muscle and that the elevation of MT acetylation in DMD acts as a disease modifier and can be targeted for therapeutic benefit. This goal of this Pathway to Independence Grant proposal is to provide the PI advanced training in muscle and heart function measurements and molecular biology techniques to pave his way to independent research while and advancing these novel discoveries towards a mechanistic understanding of role MT acetylation in striated muscle.