Control of contraction in slow-twitch mammalian muscle

Development of novel therapies to combat muscle weakness in disease and in the elderly is limited by poor understanding of the normal mechanisms of regulation of muscle contraction. Synchrotron-based small angle X-ray scattering is the most powerful technique to elucidate these mechanisms at the molecular level in intact muscles on the physiological timescale, and the upgraded ID02 beamline with Eiger 2-4M detector is currently the best facility worldwide for such studies. In this proposal we will use time-resolved X-ray diffraction and interference to determine the time course of the activation and deactivation of both the thick and thin filaments during contraction of slow-twitch muscles in near-physiological conditions, and the effect of mechanical load on the activation time courses. The results will reveal mechanisms of thick and thin filament activation in skeletal muscle, an essential step towards design and screening of novel therapeutics for muscle weakness.