Regulation of fibrosis in muscular dystrophy

The production of force and power are inherent properties of skeletal muscle, and regulated by contractile proteins within muscle fibers. However, skeletal muscle integrity and function also require strong connections between muscle fibers and their extracellular matrix (ECM). A well-organized and pliant ECM is integral to muscle function and the ability for many different cell populations to efficiently migrate through ECM is critical during growth and regeneration. For many neuromuscular diseases, genetic mutations cause disruption of these cytoskeletal-ECM connections, resulting in muscle fragility and chronic injury. Ultimately, these changes shift the balance from myogenic pathways toward fibrogenic pathways, culminating in the loss of muscle fibers and their replacement with fatty-fibrotic matrix. Hence a common pathological hallmark of muscular dystrophy is prominent fibrosis. This review will cover the salient features of muscular dystrophy pathogenesis, highlight the signals and cells that are important for myogenic and fibrogenic actions, and discuss how fibrosis alters the ECM of skeletal muscle, and the consequences of fibrosis in developing therapies.