EAGER: Exploratory Role of the Cytoskeleton in Anisotropic Regulation of Micrornas in Skeletal Muscles

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Current models of the mechanical function of skeletal muscle are founded upon studies of muscles that are generating or are subjected to forces along the length of the muscle fibers. These measurements of the longitudinal mechanical behavior of muscle have contributed to fundamental knowledge of muscle function at the tissue, cell, and molecular levels of organization. However the diaphragm, the main respiratory muscle, experiences a more complex mechanical environment in which applied forces can be resolved into longitudinal and transverse components. The potential physiological importance of mechanical loads applied to the transverse plane of the muscle in addition to mechanical forces along the length of muscle is suggested by the presence of similar populations of force-transmitting protein complexes at the lateral surface and at the ends of muscle fibers. The research will determine whether the diaphragm can detect and respond separately to longitudinal and transverse loading. This will increase our understanding of diaphragm function with age and disease. Undergraduate students also will receive research experiences form participating in the project.MicroRNAs are a recently discovered class of naturally occurring 22 nucleotides small non-coding RNAs that regulate gene expression either by degradation of target protein-coding mRNAs or by repressing translation in a mechanism similar to small interfering RNA mediated gene silencing. There is little known about the regulation of microRNAs in response to mechanical forces. Furthermore, it is not well understood how the complexity of in vivo mechanical loading in skeletal muscles such as the diaphragm alters the regulation of the microRNAs. It is also unknown whether specific cytoskeletal proteins such as desmin modulate the regulation of mechanosensing microRNAs in the ventilatory pump. The research will determine whether mechanosensing microRNAs such as let-7e-5p and miR-98-5p are regulated by two independent stretch induced signaling pathways that are dependent on the directions of applied mechanical stretch: along muscle fibers and transverse to muscle fibers. Also tested will be whether specific cytoskeletal proteins, e.g. titin and desmin intermediate filaments modulate the mechanosensitive anisotropic regulation of the let-7e-5p and miR-98-5p genes.