Determining mechanisms of redox regulation in skeletal muscle adaptation

• Applicant: Dr. Nils Burger
• Subject Area: Endocrinology, Diabetology, Metabolism ; Anatomy and Physiology ; Biochemistry ; Cell Biology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 501493132

The aim of this project is to advance our understanding of the basic biology underlying skeletal muscle adaptation with a particular focus on the mechanistic role of redox signaling. Exercise is one of the most potent strategies to prevent or reverse progression of pathologies such as cardiovascular disease, type-2 diabetes and obesity. Skeletal muscle adaptation is a response to exercise, increasing muscle performance and promoting systemic health. The adaptive response is partially mediated by the critical TCA cycle metabolite succinate, which accumulates during exercise and acts in a paracrine way on non-myofibrillar muscle cells. Importantly, succinate is also a main driver of mitochondrial reactive oxygen species (ROS) formation. ROS are recognized as essential signals controlling the adaptive response to exercise, likely via cysteine redox post-translational modifications (PTMs). Redox PTMs regulate vast metabolic pathways and cellular processes, often via coordinated regulation of entire protein networks. This project will rigorously establish the metabolome and redox proteome landscape in mouse and human SKM following exercise, to systematically characterize the mechanistic role of redox signaling in SKM adaptation. Leveraging newly developed cysteine proteomics and metabolomics technologies paired with biochemical approaches will allow to determine the molecular basis for mitochondrial SKM ROS and enable the identification of conserved redox regulated targets and pathways governing SKM adaptation. Based on this systematic analysis, mitochondrial muscle ROS will be manipulated their impact on adaptation investigated. This project will likely unveil conserved fundamental redox processes and their targets governing SKM adaptation and provide essential mechanistic insights how exercise can promote cardiovascular and metabolic health.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Edward Chouchani, Ph.D.