Third party funded individual grant
Start date : 01.01.2020
End date : 31.12.2021
Skeletal muscle is our major effector organ system for voluntary locomotion and contributes substantially to our quality of life. Muscle weakness is a symtpom not inherent to one specific disease but rather to a multiplicity of diseases of various origin, both hereditary and acquired. This is because muscle performance, i.e. force production, is the final result of a complex activation sequence involving electrical, chemical and mechanical components when muscle responds to neuronal signals. However, muscle is also an organ with an incredible plasticity, responding to exercise, hormones and external factors, like nutrition. The fact that muscle also receives hormonal signals as well as also being a site of active ‘myokine’ production embeds it in a concerted multi-organ communication system. In this way, many systemic diseases, e.g. systemic inflammation, cancer, heart disease, etc., are associated with muscle atrophy and weakness. Obesity and diabetes are other systemic metabolic diseases that are often associated with muscle weakness in humans. Type 2 diabetes usually develops as a result of obesity and the pathophysiological mechanisms of insulin resistance and glucose imbalance are major determinants of abrogated muscle anabolism and growth. However, apart from detrimental effetcs on signaling and muscle growth (e.g. atrophy), almost nothing is known about the long-term effects regarding remodelling of muscle cytoarchitecture on the cellular level that may limit maximum cellular force production.
The German partner has introduced and optimized sophisticated label-free multiphoton-based morphometry technologies applying Second Harmonic Generation (SHG) imaging and structural analysis and classification of myofibrillar lattice orientation in single fibres from muscles of various disease (animal) models (e.g. Duchenne muscular dystrophy, desminopathy, etc.). More recently, he and his team even obtained force and structure simultaneously through bioengineering of innovative systems technologies applicable to muscle tissue and cells. The American partner is a renowned neurologist and researcher who has developed novel minimally invasive diagnostic tools to assess neuromuscular health and muscle performance in humans and animals in vivo. Much of his research involves the application of electrophysiological measures, imaging modalities, and innovative bioengineering approaches to diagnose and treat such disorders. These techniques include electrical impedance myography, quantitative ultrasound, magnetic resonance imaging, and nerve and muscle excitability techniques. He is also interested in studying mechanisms of disease pathogenesis and testing new therapeutic agents that can improve function and health. In the Rutkove lab, a current focus is in the area of obesity and diabetes-induced muscle dysfunction involving the so-called BKS db mouse model that is used to model phases I to III of type II diabetes and obesity. Mice homozygous for the diabetes spontaneous mutation (Leprdb) manifest morbid obesity, chronic hyperglycemia, pancreatic beta cell atrophy and hypoinsulinemia. Obesity starts at just 3 to 4 weeks of age.
Both partners are ideally suited to complement each other to investigate the origin of weakness in obesity-related diabetic muscle dysfunction, both in regard to short-term signaling and excitability and the long-term structural remodeling aspect of myopathy to obtain a holistic picture of muscle weakness. During bilateral project visits, the German team will obtain muscle samples from BKS db mice at different ages and severity of obesity and diabetes from which the American partner has obtained quantitative measures using motor nerve and direct muscle stimulation. The latter techniques can be taught to the German partner for knowledge transfer, while the German partner will apply muscle fixation and optical clearing protocols for subsequent label-free multiphoton SHG imaging and morphometry in 3D. Those will be performed at the German partner’s institution and also during visits by the American partner and his team members (additional funding will be sought by the US side to support such visits).
To support one visit by the American partner, the FAU Visiting Professorship Program is currently being applied for on the German side (application submitted by OF, May 2019). The German team will include two short-term visits by the German PI (OF) to develop this new collaboration and to prepare and supervise the PhD student and Post-Doc together with the American partner. It will involve focused planning and transfer of muscle samples for SHG morphometry back in Germany and while being at the Harvard host, connecting with interdisciplinary seminar presentations, and preparation of joint grant initiatives.