Titin-based mechanotransduction in skeletal muscle atrophy and hypertrophy

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Our aim is to understand how mechanical input is converted into biochemical signals. We are studying titin-deficient mouse models that lack elastic or signaling domains within the titin protein. Building on these animal models generated in the first funding period, we will extend the phenotypic analysis of the titin kinase domain (TK) knockout to investigate the molecular basis of the TK-dependent exercise intolerance, which recapitulates symptoms found in patients with glycogen storage disease. Therefore, we will also monitor glycogen and glucose homeostasis in the TK knockout mouse. Towards understanding the molecular basis of the metabolic and trophic phenotype, we will investigate atrophy/hypertrophy signaling in the TK knockout mouse after denervation and exercise, respectively and employ a cell culture-based system to resolve how the kinase domain is activated. We believe that we will be able to couple these findings to the protein-expression results we obtained in the hibernating grizzly bear during the first funding period. We will analyze candidate proteins that cause impaired mechano-transduction in the mouse and the candidate proteins associated with lack of disuse atrophy in grizzly bear. Understanding trophic signaling that protects muscle from atrophy and the role of titin as a mechanosensor, will help us not only to elucidate primary titin-based myopathies, but also to understand atrophy in bedridden patients, spaceflight, and the sedentary elderly.