MECHANOSENSING AND MUSCULAR DYSTROPHY

TRPC6 as a mechano-sensor and therapy target

Of the various forms of muscular dystrophy, Duchenne’s is the most severe, with patients lacking the key mechano-signaling protein dystrophin. This results in progressive skeletal muscle deterioration and weakness, leaving individuals largely immobile by early teens. Heart disease progresses and is a major cause of mortality in ensuing decades. We found that the non-selective cation channel – TRPC6 – plays a key role in hyperactive mechano-sensing in dystrophic myocytes and muscle in the heart, leading to excess calcium entry and force responses. Suppression of this channel by gene deletion appears protective, and ongoing work is examining the potential for small molecule inhibitors to achieve similar effects. The work integrates bio-engineering studies of muscle cell function and force development with molecular biology and genetic models.