Third party funded individual grant
Start date : 01.11.2013
End date : 30.08.2018
Skeletal muscle is one of the most plastic human organs adapting to exercise but also to chronic disease. Chronic degenerative/inflammatory muscle diseases are associated with progressive weakness and immobility. Although specific signaling pathways may fingerprint each individual disease mechanism, chronic remodeling of tissue and cell architecture is the main common principle. Tissue fibrosis is well understood, however, cellular detailed changes in skeletal muscle fibre cytoarchitecture have not been addressed in detail. We believe that at least half of the weakness in chronic muscle disorders is accounted for by cellular remodeling, e.g. fibre branching or deranged myofibrillar lattice geometry. In this project, we aim to apply state-of-the art multiphoton Second Harmonic Generation, SHG microscopy in two animal models of inherited degenerative disease: mdx mice lacking dystrophin (model for Duchenne muscular dystrophy, DMD) and desmin-null and mutated desmin-knock-in mice (model for desminopathy). Especially the latter model has never been studied before using quantitative subcellular morphometry that is capable of revealing insights into structural alterations in degenerative protein aggregation myofibrillar myopathies in humans. For this, we will perform a detailed age-related study using single fibres from young to old mice and subject them to our advanced imaging technology and structure analysis. As a special goal, we will also combine optical morphometry with recordings of isometric force production in the same cells to provide a calibration for our goal to use SHG imaging in muscle fibres and tissue as a means to predict force loss and weakness by optical means. The project will not only contribute to our understanding of molecular and biophysical origins of progressive muscle weakness but also provide a novel powerful imaging tool to the muscle research community.