Project Details
Projekt
P04 HyperPig. Metabolic health effects associated with muscle hypertrophy in pigs
Applicants
Dr. Arne Hinrichs; Professor Dr. Eckhard Wolf
Subject Area
Endocrinology, Diabetology, Metabolism
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 536691227
Global skeletal muscle hypertrophy has anti-obesity and anti-diabetes effects. The underlying mechanisms are poorly understood. Most of the current research is focussed on identifying circulating regulators such as myokines but there is hardly any research that investigates the relationship between skeletal muscle, white adipose tissue, and glucose homeostasis from a metabolic perspective. The aim of the project is to use advanced methods of metabolic research to elucidate the metabolic mechanisms that explain the association between high muscle mass, low fat mass and improved glucose homeostasis. We will conduct this research in pigs because blood vessels for all major organs can be easily cannulated. This will allow us to study how muscle hypertrophy redirects metabolic fluxes within the organism using arteriovenous metabolomics. Moreover, porcine metabolism is more like human metabolism and the pig is a good model to perform tracer experiments that will be performed in humans in the second funding period. Specifically, we have 4 objectives: First, we will induce muscle hypertrophy by genetically engineering myostatin-deficient (MSTN KO) Göttingen Minipigs. Second, we will compare the muscle size, body fat, and metabolic health of the MSTN KO pigs with wild-type pigs. Myostatin is a growth factor for skeletal muscle and its loss results in a very prominent phenotype of muscle hypertrophy and reduction in fat mass. Third, we will test, whether the administration of ß2-agonists is a suitable approach to induce fat-to-muscle repartitioning effects in pigs and can have a potential clinical relevance for human patients suffering from the metabolic consequences of muscle atrophy. Forth, we will use arteriovenous metabolomics in combination with tracer-based flux analysis to determine the fate of glucose and amino acids in Göttingen Minipigs pigs with muscle hypertrophy and wild-type controls. From the increased energy and metabolite demand of the hypertrophying muscle, we hypothesize alterations of circulating amino acids, free fatty acids, glucose and lactate. Resulting from decreased metabolite supply, we expect a reprogramming of other tissues and organs which results in a decrease in fat mass. The utilization of amino acids and especially branched-chain amino acids, who are seen as a metabolite risk factor will be determined in muscle and fat biopsies following a U-13C-leucine-tracer infusion. Arteriovenous metabolomics will be performed in combination with U-13C-glucose-tracer to determine glucose and metabolite flux in specific tissues. By characterizing the metabolic mechanisms that explain the association between muscle hypertrophy, fat loss and improved glucose homeostasis, we will contribute to the development of drugs and interventions for over one billion people with obesity and diabetes globally.
DFG Programme
Research Units
