Energimetabolisme og nye angrepspunkter for legemidler
Type 2-diabetes og fedme er økende helseproblemer i hele verden. Et tidlig tegn på utvikling av type 2-diabetes er insulinresistens i skjelettmuskulatur og dermed nedsatt glukosetoleranse. Skjelettmuskulaturen spiller en sentral rolle i å opprettholde glukosehomeostase og er også viktig i forhold til lipidomsetningen i kroppen. Vi studerer primært cellulære mekanismer bak insulinresistens i human skjelettmuskel og hvordan disse mekanismene kan påvirkes – blant annet av potensielle legemidler som modulerer metabolske kjernereseptorer og ved trening.
- Molekylære mekanismer i skjelettmuskel relatert til insulinresistens og type 2-diabetes mellitus
- Kjernereseptorer som angrepspunkt for legemidler
- Cellulære mekanismer for treningseffekter i muskel
- Lipiddynamikk og insulinresistens
- Remodellering av energimetabolisme
- Fettsyreanaloger med effekter i mitokondriene
Cellular mechanisms of exercise effects in skeletal muscle
1. Chronic and acute effects of electrical pulse stimulation on storage and oxidation of fatty acid in myotubes from different donor groups
Obesity is a risk factor for development of many clinical complications - including insulin resistance and type 2 diabetes (T2D). For many individuals, physical activity is a good treatment strategy, although we do not completely understand the molecular mechanisms involved. In this project we will study both chronic and acute effects of electrical pulse stimulation (EPS) on fatty acid metabolism in myotubes from lean, nondiabetic, and obese subjects with and without T2D. We propose that various patterns of EPS (both separate and combined high- and low-frequency EPS) may show different effects on fatty acid metabolism measured by ”fuel-handling” methods using radiolabeled precursors, and by gene and protein expressions. Furthermore, we believe that the responses observed will vary between myotubes from different donor groups.
Collaboration with: Cédric Moro, INSERM/Université Paul Sabatier
2. Adaptations in human skeletal muscle cells using two different in vitro approaches: innervation and electrical pulse stimulation (EPS)
Innervation of human myotubes in vitro by co-culturing with embryonic rat motor neurons (spinal cord segments) is an approach that might overcome some of the limitations of quiescent cultured human skeletal muscle cells. Additionally, motor neuron activation can be replaced by electrical pulse stimulation (EPS) in culture. In this project we will characterize two in vitro approaches used to induce contractions; innervation with embryonal spinal cord implants and EPS. Changes in energy metabolism will ce compared as well as expression of muscle fiber type genes (myosin heavy chains), myokine expression and secretion and functional studies on energy metabolism using radiolabeled substrates.
Collaboration with: Tomaz Mars, University of Ljubljana, Faculty of Medicine, Ljubljana, Slovenia
Remodeling of energy metabolism
Futile cycling in human skeletal muscle cells? Role of different fatty acids, hypothermia and AMPK ablation?
It has previously been shown that interventions using omega-3 fatty acids, calorie restriction and cold exposure may prevent obesity in mice fed high-fat diets. This was associated with strong hypolipidemic and insulin-sensitizing effects and synergistic induction of mitochondrial oxidative phosphorylation (OXPHOS) and fatty acid oxidation in white adipose tissue. These changes occurred without induction of uncoupling protein 1 (UCP1) and suggested the involvement of a futile substrate cycle in white adipocytes, which is based on lipolysis of intracellular triacylglcyerol (TAG) and re-esterification of fatty acids, in association with induction of mitochondrial OXPHOS capacity, fatty acid β-oxidation and energy expenditure.
We have previously shown that pretreatment of differentiated human skeletal muscle cells (myotubes) with eicosapentaenoic acid (EPA) promoted increased uptake of fatty acids and increased triacylglycerol (TAG) accumulation, compared to pretreatment with oleic acid (OA), and also positively influenced energy formation (fatty acid betaoxidation) and metabolic switching of myotubes.
This project examines whether EPA can increase free fatty acid - TAG (futile) cycling in human skeletal muscle cells compared to other fatty acids. The effect of hypothermia and inactivation of AMPK (will promote decreased FA oxidation) on futile cycling will also be examined.
Collaboration: Jan Kopecký, Institute of Physiology, CAS, Praha, Czech Republic
The "Energy metabolism unit" (PI: J. Kopecký) examines the importance of a "futile" cycle involving triacylglycerol hydrolysis and re-esterification of fatty acids in adipocytes from white adipose tissue for resistance to obesity and associated metabolic disorders.