UC San Diego

The disproportionate loss of muscle force with aging and disuse atrophy compared to the loss of muscle mass is not yet completely understood. In addition to well-established neural and contractile determinants of force loss, remodeling of the extracellular matrix (ECM) has been recently shown in animal models to be another important contributor. In-vivo human studies exploring the structural remodeling of the ECM and its functional consequences are lacking due to the paucity of appropriate imaging techniques. This study focuses on the development and application of advanced Magnetic Resonance Imaging (MRI) methods to elucidate the mechanisms of loss of force with aging and disuse atrophy with the focus on ECM. Functional changes are investigated by strain and strain rate tensor mapping of muscle under different contraction paradigms using Velocity Encoded Phase-Contrast MRI. Methodological advances include improvements in hardware and software control of the dynamic studies. To overcome the limitation of long scan times, compressed sensing MR acquisition and reconstruction framework to reduce scan times to under a minute were developed. A multi-step automated analysis pipeline to extract 3D strain/strain rate tensors from the velocity images was implemented to process the large dynamic volumes. Strain indices reflecting the material properties of the ECM were shown to correlate with force loss leading to a hypothesis that shear strain may serve as a surrogate marker for lateral transmission of force. Diffusion tensor imaging has been applied previously to study skeletal muscle fiber architecture. The resolution of the images precludes direct inferences to be made about the microstructure. To address this limitation, bicompartmental and Random Permeable Barrier models of diffusion were applied to the diffusion data obtained with spin-echo and custom-developed stimulated echo echo-planar-imaging sequences respectively. Model derived parameters (fiber diameter, wall permeability) obtained from fitting time-dependent diffusion data were in physiologically reasonable range, with potential for tracking age related changes in muscle microstructure. The developed imaging and modeling techniques were applied to a cohort of young/senior subjects and to longitudinal tracking of disuse atrophy induced by Unilateral Limb Suspension. These studies may potentially provide the causal link between age- and disuse-related structural remodeling and its functional consequences.