Muscle Research Group
Energy metabolism related to type 2 diabetes and obesity
Human cultured skeletal muscle cells: mitochondria are red, nuclei blue and lipid droplets green.
Energy metabolism and drug targeting
The main focus of the research group is to study skeletal muscle molecular mechanisms related to insulin resistance and type 2 diabetes mellitus (T2D). Skeletal muscle is of particular interest in metabolic diseases and disease prevention since it is the major regulated energy consumer in the human body. We study how cellular mechanisms underlying insulin resistance in human skeletal muscle can be affected by pharmacological intervention with potential drugs that e.g. modulate lipid metabolism via metabolic nuclear receptors, by affecting thermogenic/futile processes and by exercise in vitro. In addition to skeletal muscle, cells from other organs of importance in T2D (e.g. liver, adipose tissue) are included in some of the projects.
Main research topics:
- Cellular mechanisms of exercise effects in skeletal muscle
- Modulation of energy metabolism
- Nuclear receptors and nuclear receptor regulators as drug targets
- Beta2-adrenergic receptors as drug target in skeletal muscle
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 study effects of an in vitro-exercise model (electrical pulse stimulation, EPS) on energy metabolism and myokine (exerkine) secretion in human myotubes from different donor groups, e.g. lean, well-trained and obese donors, as well as patients with T2D or with spinal cord injuries. Cross-talk between exercising muscle and other cell types are studied using conditioned media.
- n-3 fatty acids to improve muscle function. We study the effects of n-3 fatty acid supplementation in individuals with obesity and healthy controls (compared to placebo) on energy metabolism in skeletal muscle cells isolated before and after two months of intervention. Treatment of muscle cells from lean subjects with eicosapentaenoic acid (EPA) has previously been shown to increase energy metabolism and futile cycling in myotubes. It is proposed that the intervention in this project may have positive effects on lipid metabolism and insulin sensitivity, especially in cells established from the obese subjects. Moreover, cellular properties such as proliferative capacity and differentiation, as well as myokine secretion will be examined.
- Modulation of SERCA activity in myotubes. Muscle contraction and relaxation depends on the release of Ca2+ from the sarcoplasmic reticulum and reuptake of Ca2+ by sarcoplasmic reticulum Ca2+ ATPase (SERCA) pumps. Prolonged activation of SERCA due to alteration in cytosolic Ca2+ results in excessive consumption of ATP. The SERCA pump activity can be further enhanced by the presence of proteins such as sarcolipin. Recent studies have shown the possible role of sarcolipin in regulating skeletal muscle thermogenesis and energy metabolism by promoting decoupling of the SERCA pump from Ca2+ transport, which provides increased ATP hydrolysis and heat production. The effects of SERCA modulation on energy metabolism in human myotubes will bestudied with and without in vitro exercise. In this project we will also study if SERCA modulation is involved in the thermogenic effect of trijodothyronin (T3) in skeletal muscle.
- Role of AMPKα2 in skeletal muscle. Mammalian AMP-activated protein kinase (AMPK) α2 catalytic subunit has been shown to control whole-body insulin sensitivity. The effects of inactivation of AMPKα2 are examined in myotubes established from AMPKα2 knock-out mice. We propose that loss of AMPKα2 will impair mitochondrial biogenesis and fatty acid oxidation, promote lipid storage and reduce insulin sensitivity of the cells.
- HDL as a modulator of skeletal muscle energy metabolism. Physical activity affects the distribution of high density lipoprotein (HDL) subfractions in blood plasma, and biological activities of HDL have been described to vary depending on the subfractions of HDL being examined. It has also been shown that HDL may affect glucose metabolism and that HDL could modulate cellular respiration in skeletal muscle. We study molecular mechanisms for increased energy metabolism in human skeletal muscle cells by treatment with apolipoprotein A-I (ApoA1) and various subfractions of HDL (HDL2 and HDL3), as well as HDL isolated from individuals with different exercise status and HDL with modified composition.
- Role of diacylglycerol acyltransferase (DGAT) in skeletal muscle. DGAT 1 and 2 catalyse the final step in triacylglycerol (TAG) synthesis, the esterification of fatty acyl-CoA to diacylglycerol. Despite catalysing the same reaction and being present in the same cell types, they exhibit different functions on lipid metabolism in various tissues, and their roles in skeletal muscle remain poorly defined. We are investigating how selective inhibitors of DGAT1 and DGAT2 affect lipid metabolism in human skeletal muscle cells from lean and well-trained subjects, and obese subjects with T2D. We propose that muscle cells from various donor groups will respond differently with respect to energy metabolism and insulin sensitivity.
Metabolic nuclear receptors e.g. LXRs, PPARs and thyroid receptors (TRs) are important regulators of cholesterol, lipid and glucose metabolism as well as thermogenesis in the body, and are also involved in regulation of inflammation and development of atherosclerosis. This explains why metabolic nuclear receptors are potential hot drug targets in the battle against T2D and obesity. More specifically, we currently address the metabolic role of regulation of PPARs through SUMO-specific protease 2 (SENP2) in both human myotubes and adipocytes.
Chronic administration of long-acting beta2-adrenergic agents has been shown to increase insulin sensitivity in vivo and prevent metabolic syndrome.
We study the effects of beta2-stimulation on glucose uptake, energy metabolism and signalling pathways in cultured skeletal muscle cells, as well as possible long term effects on muscle protein synthesis and hypertrophy.