Skeletal muscle exemplifies structure-function relationships in biology. The organization of sarcomeres follow
hierarchical ordering to form long contractile cells, bundled in extra-cellular matrix, to form larger fascicles and
ultimately whole muscles. The tight relationship between structure and function allows muscle performance
(and disease) to be inferred from its microstructure. For example, fiber area is directly related to isometric force
production in muscle. With injury, microstructural changes in muscle fiber area (size), fibrosis (accumulation of
extracellular matrix), membrane damage (permeability), and inflammation (edema) are observed, and impair
muscle function. Muscle biopsy, followed by microscopic examination of the tissue (histology), is the gold
standard to diagnose and monitor muscle health and disease. This tool is invasive, requiring a large bore
needle and tissue removal under sterile conditions, which makes it painful and costly. Therefore, biopsy is not
conducive to serial monitoring of muscle health. It is also semi-quantitative, and often difficult to extrapolate to
the entire muscle, limiting its scientific and clinical value. For these reasons, there is a need for noninvasive
assessment of muscle microstructure, which would facilitate the quantitative examination of muscle injury over
time. Magnetic resonance imaging (MRI) has been used to noninvasively quantify changes in volume, fat
distribution, and water content in muscle. Diffusion tensor imaging (DTI) is a version of MRI that measures
anisotropic diffusion of water, which is related to tissue microstructure, but tends to yield non-specific changes
regardless of the injury or disease state. The key reason for this lack of specificity is that the explicit
relationships between microstructure and diffusion have not been rigorously studied, nor carefully calibrated.
To address this gap in knowledge, the purpose of this proposal is to compare muscle microstructure and MRI
diffusion properties of muscle in novel and tightly controlled computer simulations, precision engineered
phantoms, and animal models of muscle injury and disease. Our central hypothesis is that DT-MRI can be
directly related to muscle microstructural changes, when appropriate pulse sequences are used to uncouple
complex pathology. Aim #1 will use computer-based simulations of muscle structure and biochemistry to
carefully understand how diffusion is related to multiple muscle microstructural changes. Aim #2 will utilize 3D
precision-engineered models to relate diffusion to muscle structure in real-world DT-MRI experiments. These
experiments will be integrated into a final in vivo set of experiments (Aim #3), which are designed to test the
accuracy of DT-MRI to uncouple complex microstructural changes in the presence of muscle atrophy,
inflammation, and degeneration. These experiments will elucidate the understudied relationships between
microstructure and diffusion in muscle. The long-term goal is to serially quantify muscle microstructure non-
invasively. This approach is innovative in that it combines state-of-the art imaging, simulation, nanofabrication,
and morphology methods to generate a clinically meaningful measurement tool.
