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, heart 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:

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 energy metabolism

  • Inkretins effects on muscle- and bone function. GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic peptide) are incretin hormones that are produced in the small intestine and are broken down by the enzyme dipeptidyl peptidase 4 (DPP-4). The secretion of GLP-1 and GIP increases after a meal and contributes to increased insulin secretion from the pancreas and helps to regulate/stabilize blood sugar levels. GLP-1 analogues (incretin mimetics) and DPP-4 inhibitors (gliptins) are used in the treatment of type 2 diabetes (T2DM), but GLP-1 analogues (e.g. semaglutide) have received much media attention due to their use and efficacy/side effects in the treatment of obesity. In addition, drugs have been developed that are combined GIP/GLP-1 analogues (e.g. tirzepatide) with weight-reducing potential. We are studying whether inkretins and inkretin mimetics affect cell differentiation, atrophy, as well as glucose and fatty acid metabolism. We also want to study whether GIP/GLP-1 analogues and/or DPP-4 inhibitors affect the cysteine ​​protease legumain in the cells.
  • Modulation of Piezo1 activity in myotubes and osteoblasts. The mechanosensitive ion channel Piezo1 is activated by the agonist Yoda1. This activation induces intracellular Ca²⁺ influx in various tissues, including skeletal muscle and bone. We are studying the metabolic and possibly regulatory role piezo1 has in myotubes and osteoblasts. We have observed that Yoda1 treatment of myotubes modulated energy substrate metabolism and mitochondrial function pointing at increased oxidation.
  • 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 (protease) called legumain (asparaginyl endopeptidase), 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 the substrate occurs. Legumain is involved in regulation of several biological possesses in the body or tissue homeostasis including hematopoiesis, immune regulation, bone remodeling, and kidney function. Furthermore, legumain has been shown to be involved in the pathogenesis of various diseases, like cancers, cerebrovascular diseases, cardiovascular diseases, neurogenerative diseases, osteoporosis and fibrosis. Inhibiting legumain by drugs is therefore an interesting strategy for therapeutic treatment.

Legumain and cell differentiation. Made by R.Solberg
Legumain and cell differentiation. Made by R.Solberg

In bone remodeling, we have shown that legumain inhibits differentiation of bone-marrow mesenchymal stromal cells (BMSCs) to osteoblasts (bone-forming cells), thus inhibiting the formation of new bone in the skeleton. Low level or inhibition of legumain is therefore a prerequisite for damage repairing of the skeleton. In contrast, high level of legumain will drive differentiation of the stem cells to fat cells (adipocytes).

In this project, we study the effects of various mediators, hormones, marketed or potential drugs on regulation of legumain in BMSCs during osteoblast differentiation and how this affects the differentiation, production of extracellular matrix proteins or energy metabolism.

Regulation of cyclic nucleotide signaling in the heart

Heart failure (HF) is a common and serious condition where the heart cannot pump enough blood to meet the body’s needs. It is usually divided into two main types. In HFrEF (heart failure with reduced ejection fraction, or systolic HF), the left ventricle cannot contract effectively, so less blood is pumped out with each beat. In HFpEF (heart failure with preserved ejection fraction, or diastolic HF), the heart becomes stiff and cannot relax and fill properly with blood between beats. In both cases, the result is inadequate blood supply to the body. While HFrEF has been studied for several decades and has multiple established treatment options, HFpEF has only been systematically explored in the last 20 years. Effective therapies for HFpEF remain very limited, and sodium–glucose cotransporter 2 (SGLT2) inhibitors are currently the only clearly recommended first line treatment.

In order to find better heart failure (HF) treatment, we need better understanding of the mechanisms of myocardial function in healthy and failing hearts. Cyclic nucleotides (cAMP and cGMP) are important signaling molecules highly involved both in HFrEF and HFpEF. It is known that receptors increasing the same signaling molecule can cause differential effects, i.e both beta-adrenoceptor (beta-AR) and prostaglandin receptor stimulation increase cAMP, but only beta-AR stimulation cause inotropic response. Similarly, stimulating the two natriuretic peptide receptors GC-A and GC-B with C-type natriuretic peptide (CNP) and brain natriuretic peptide (BNP), respectively, both increase cGMP, but only CNP, not BNP, cause effects on contractility. Phosphodiesterases (PDEs), breaking down cAMP and cGMP, are key regulators of cyclic nucleotide signaling involved in compartmentation of functional effects. However, regulation by PDEs is not the complete answer to why some receptors cause contractile effects, whereas others do not. A plausible explanation for these differential effects could be different location of receptors and different intracellular binding partners. Thus, in this project we study the effect of PDEs and interacting proteins on cyclic nucleotide-mediated effects especially related to changes in heart failure.

Mechanism of action of novel GC-A activators for the treatment of cardiovascular diseases

Natriuretic peptides have pleiotropic effects in the cardiovascular system causing natriuresis, diuresis, vasodilation and anti-hypertrophic effects. In this project we aim to find novel GC-A activators for the use in treatment of different cardiovascular diseases. This is a collaborative project together with the group of professor Finn Olav Levy at The Medical Faculty, UiO.