Control of Contraction in Skeletal Muscle by Thick Filament Mechano-sensing

Development of novel therapies to combat muscle weakness in disease and in the elderly has been limited by poor understanding of the normal mechanisms of regulation of muscle contraction. Synchrotron-based small angle X-ray scattering provides a uniquely powerful approach to investigate these mechanisms at the molecular level in intact muscles on the physiological timescale. The upgraded ID02 with the Eiger 2-4M detector currently offers the best facility worldwide to determine the regulatory structural changes in the myosin-containing thick filaments following single action potential stimulation of isolated mammalian muscles in physiological conditions, and their dependence on muscle load. No previous study has looked at thick filament mechano-sensing in mammalian muscle during physiological activation by a single action potential. The results will establish a structural and functional framework for testing small molecules as potential therapeutics for muscle weakness in man.