Characterizing metabolism in hypertrophying muscle

• Applicant: Professor Dr. Franz Schilling, since 4/2024
• Subject Area: Anatomy and Physiology ; Biochemistry ; Animal Physiology and Biochemistry ; Nuclear Medicine, Radiotherapy, Radiobiology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 537214107

Obesity accounts for 4 million deaths globally per year and is strongly related with physical inactivity and loss of muscle mass and strength. Resistance exercise is a strong stimulus for muscle hypertrophy and a concomitant reduction in body fat. Next to obesity, other muscle wasting diseases involving muscle protein degradation (i.e. atrophy) could benefit from a better understanding of metabolic changes involved in muscle hypertrophy. A direct link between muscle hypertrophy and leanness is not evident, but it is clear that individuals with hypertrophying muscles have a surplus of energy consumption. This effect is also seen in animals, where muscle hypertrophy, due to (natural or induced) genetic mutations, is associated with leanness and low body fat. Little is known however about how muscle metabolism changes when muscles hypertrophy. Recent evidence indicates that muscle hypertrophy is accompanied by a higher uptake of glucose, an increase in the glycolytic flux and in lactate production. Interestingly, this metabolic reprogramming is highly similar to that in tumors. Both hypertrophic muscles and tumors take up more glucose and produce more lactate compared to normal tissue even under aerobic conditions. This metabolic reprogramming to aerobic glycolysis is known as Warburg metabolism. In this proposal, we aim to obtain insight in the metabolic reprogramming in muscle hypertrophy in two mouse models using a combination of methods that have been employed previously in cancer metabolism measurements. We do this in a mouse model involving overload of specific muscles and in a double knockout muscle hypertrophy model. To obtain complementary dynamic read-outs of Warburg metabolism, we will first monitor glucose uptake after injection with glucose analog [18F]FDG, using PET imaging. Secondly, hyperpolarized (HP) [1-13C]pyruvate MR spectroscopy/MRI measurements will be employed to monitor pyruvate-to-lactate conversion. Third, MR spectroscopy measurements will be performed to obtain insight in levels of, and changes in, muscle-related metabolites. This includes insight in the build-in of glucose into glycogen, levels of intra- and extramyocellular lipids and build-up rates of phosphocreatine. This is complemented with ex vivo analysis of muscle tissue (transcriptomics, proteomics, histochemistry) and high-resolution NMR spectroscopy. This project will further the knowledge on how metabolism changes in hypertrophic muscle and can give insights in how to treat or help managing metabolic diseases like diabetes, sarcopenia, Duchenne muscular dystrophy and cachexia in cancer patients. Additionally, this information can help optimizing training for weight loss and increase understanding of how to get the most out of physical training. Obesity is a problem in a growing number of populations around the world and getting insight in how muscle hypertrophy can help people with metabolic diseases or obesity, can have a significant impact on society.

• DFG Programme: Research Grants
• Co-Investigators: Professor Dr. Karsten Hiller; Professor Dr. Henning Wackerhage
• Ehemaliger Antragsteller: Dr. Frits van Heijster, until 4/2024