Biochmechanics of MFM: a multi-scale approach

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Myofibrillar myopathies (MFM) are associated with mutations in genes encoding cytoskeletal proteins and linker proteins, e.g. desmin or plectin. Most of these proteins connect adjacent myofibrils as well as myofibrils to Z-lines or other important cytoskeletal components and thus, ensure proper anchorage in biomechanically active muscle. Disruptions of these linkages are expected to result in vast disturbances of biomechanical properties, including elasticity, active force production, lower mechanical stress resistance that can induce cell damage and insufficient repair. Although the common symptom in all patients with MFM is muscle weakness, there is almost no information at hand as to how muscle is affected at different structural and functional levels within the organ and what is the molecular cause of the muscle weakness. The present Z-Project unites a consortium of researchers with renowned expertise in muscle biomechanics at all levels of organ function. In a multiscale approach, we will systematically investigate active and passive biomechanical properties of muscle function at the level of whole muscles, small muscle fibre bundles and single muscle fibres as well as biomechanical response to cyclic stretch and focal adhesion points in primary myoblasts. Using the established mouse models within FOR1228 (Des-KO, DesR350P-KI hetero-/homozygous, conditional Plct-MCKCRE7cKO, isoform-specific Plct-KO P1b/P1d) as well as samples from MFM patients, our aim is to identify biomechanical dysfunction several structural levels. Furthermore, we will test the hypothesis that MFM share common functional patterns despite their underlying molecular heterogeneity.