Microtubule Mechanotransduction Tunes Musculoskeletal Function: Science Fridays Talk
Microtubule Mechanotransduction Tunes Musculoskeletal Function
Christopher W. Ward, PhD
Associate Professor, Department of Orthopedics, University of Baltimore
Friday, April 20, 2018
For the past 16 years my research program has focused on the mechanisms by which local calcium (Ca2+) signals contribute to physiological and pathological adaptations in striated muscle. Since 2009, I have focused much attention on the mechanisms by which mechanotransduction modulates local Ca2+ signaling. Our initial discoveries were in heart where we revealed that microtubules (MT) were essential cytoskeletal elements for the activation of stretch activated Ca 2+ sparks. To enable new discoveries in heart and skeletal muscle we developed novel research tools for the mechanical manipulation of single enzymatically isolated muscle cells.
Enabled by our novel techniques we discovered a MT mechanotransduction pathway in striated muscle which linked the mechanical force of stretch/contraction to a burst of reactive oxygen species (ROS) from NADPH oxidase2 (Nox2); a pathway we term X-ROS signaling. Our discoveries in both heart and skeletal muscle place Glu-tubulin, a post-translational modification (PTM) to a-tubulin, central to the regulation of MT dependent X-ROS mechanotransduction in health. Furthermore, we link the disease dependent increase in MT density and its level of Glu-modified tubulin to the deleterious excess in X-ROS and Ca2+ signals that underscore workload injury in dystrophic heart and skeletal muscle. The significance of our findings was seen when acute in vivo targeting of Glu-tubulin effectively protected both skeletal muscle and heart from workload induced contraction injury in the mdx model of Duchenne muscular dystrophy (DMD). Our recent work focuses on extending our acute MT targeted interventions to chronic trials, testing the hypothesis that these treatments will have a broad impact on muscle function.
In other work, we have transitioned to bone where the mechanisms linking mechanical cues to bone formation are not fully defined. Here we have identified MT mechanotransduction through X ROS as an integral pathway that regulates the mechano-responsiveness of osteocytes to regulate bone formation.Please contact Gwen Dodd in the Office of Research and Sponsored Programs at email@example.com with questions.