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Energy Metabolism in Health and Disease (MetHealth)

Energy metabolism and new drug targets for therapy

Human cultured skeletal muscle cells: mitochondria are red, nuclei blue and lipid droplets green.

Energy metabolism and drug targeting

Lifestyle and age-related diseases such as type 2 diabetes, obesity and osteoporosis are increasing health problems worldwide. Skeletal muscles play a central role in maintaining glucose homeostasis and are also important in relation to lipid turnover in the body. Bone-building cells (osteoblasts) are important for maintaining the bone structure. We primarily study cellular and molecular mechanisms in skeletal muscle cells and osteoblasts, to detect potential new target molecules for drugs, and how these mechanisms are affected by marketed and potential new drugs and by exercise.

GOOD HEALTH AND WELL-BEINGINDUSTRY, INNOVATION AND INFRASTRUCTURE17 PARTNERSHIPS FOR THE GOALS

Researchers in MetHealth contributes towards the United Nations (UN) sustainability developmental goals. Our research projects related to energy metabolism and type 2 diabetes/obesity as well as bone health are in line with goal 3: "To ensure healthy lives and promote well-being for all at all ages". Pharmacological interventions, drug development, establish new technologies (cell models), innovation and industry collaboration are in agreement with goal 9:  "Sustainable innovation and infrastructure". International collaboration and partnerships are important to reach the aims of many of our projects to get more knowledge about prevention and future treatments of important metabolic disorders are are in agreement with goal 17: "Partnerships for the goals".

 

Main research topics:

 

Development of three-dimensional cultures of primary human skeletal muscle cells

At present, 2D cell models have been the most used cellular models to study skeletal muscle energy metabolism. However, the transferability of the results to in vivo might be limited. This project aims to develop and characterize a human skeletal muscle 3D cell model (myospheres) as an easy and low-cost tool to study molecular mechanisms of energy metabolism.

Cellular mechanisms of exercise effects 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.

    Crosstalk between skeletal muscle and bone

    The interplay between skeletal muscle and bone is of high interest, partly due to the close proximity of the organs, but also the fact that these organs are major regulators of whole-body energy metabolism. In addition to mechanical communication between bone and skeletal muscle, recent studies indicate an emerging role of biochemical communication (crosstalk). Factors released by skeletal muscle are called myokines. Moreover, studies have shown that dysregulation of one organ affects the other organ, for example, muscle atrophy (muscle wasting) results in osteoporosis. In this project we are studying the effect of exercise in vitro on modulation of energy metabolism in various bone-derived cells (e.g. osteoblasts), as well as the effect the protease legumain on skeletal muscle energy metabolism.

    Thus, deeper understanding of crosstalk between skeletal muscle and bone has the potential of exploring new drug targets for therapies of sarcopenia and osteoporosis.

    Possible biochemical crosstalk between skeletal muscle and bone. The figure shows myokines released from skeletal muscles that could affect bone, and effects from bone-derived factors on skeletal muscle. Inhibition is illustrated as red arrows while the green arrows illustrate stimulation. The blue arrow is unknown mechanism. The figure has been made by postdoc Ngoc Nguyen Lunde

    Drugs and drug targets to modulate of energy metabolism in skeletal muscle

    • 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, retinoic acid receptors (RARs) 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 drug targets in the battle against T2D and obesity.  

    The cysteine protease legumain as a drug target

    The main focus of this projects is a proteolytic enzyme called legumain, which belongs to the class of cysteine proteases together with cathepsins and caspases. When legumain cleaves its substrate proteins, either activation or inactivation/degradation of a particular substrate occurs. Legumain is involved in regulation of several biological possesses in the body or tissue homeostasis. Furthermore, legumain has been shown to be involved in pathogenesis of various malignant and nonmalignant diseases, including hematopoiesis, immune regulation, bone remodeling, kidney function, cerebrovascular diseases, cardiovascular diseases, neurogenerative diseases, and fibrosis. Inhibiting legumain by drugs is therefore an interesting strategy for therapeutic treatment.

    In bone remodeling, we have shown that legumain inhibits differentiation of bone-marrow mesenchymal stromal cells (BMSCs) into osteoblasts (bone-building cells), thus inhibiting the formation of new bone substance in the skeleton. Low level or inhibition of legumain is therefore a prerequisite for damage repair of the skeleton. In contrast, the presence of high legumain concentration, the stem cells will differentiate into fat cells.

    In this project, we study the effect of various mediators, hormones, or drugs on regulation of legumain in differentiating osteoblasts and how this affects differentiation, production of extracellular proteins or energy metabolism.

    Published Feb. 15, 2011 1:58 PM - Last modified Jan. 26, 2024 6:18 AM

    Contact

    Group leader:
    Hege Thoresen

    Participants

    Detailed list of participants